Salt of a sulfonic acid containing clopidogrel and use thereof for the production of pharmaceutical formulations

ABSTRACT

The present invention relates to the salt of a sulfonic acid with clopidogrel and pharmaceutical formulations comprising this salt.

The present invention relates to the salt of a sulfonic acid withclopidogrel, a method for preparing the same and the use thereof forpreparing pharmaceutical formulations. The present invention furthercomprises active ingredient particles with clopidogrel or apharmaceutically acceptable salt thereof.

Clopidogrel (5-methyl-α-(4,5,6,7-tetrahydro[2,3-c]thienopyridyl)(2-chlorophenyl)acetate) is known from EP-A-0 099802 as an active ingredient. Clopidogrel acts as a platelet aggregationinhibitor and may therefore be used for the prevention of thromboembolicevents such as a stroke or a myocardial infarction.

EP-A-0 281 459 proposes to use inorganic salts of the (S)-(+)clopidogrel, particularly (S)-(+) clopidogrel hydrogen sulfate inpharmaceutical formulations. This document also discloses organic saltsof clopidogrel, but these are described as amorphous and/or hygroscopicand difficult to purify.

The (S)-(+) clopidogrel hydrogen sulfate used in pharmaceuticalformulations has the disadvantage that concentrated sulfuric acid isrequired for preparation thereof and that the resulting products reactin a superacidic manner because of the acidic proton. These acidiccharacteristics affect the compatibility with many pharmaceuticaladjuvants and thus the stability of drug forms resulting therefrom.Therefore, there is a need for stable forms of clopidogrel which areeasy to purify and may be processed readily with differentpharmaceutical adjuvants such as drug carriers and additives.

Therefore, it is one object of the present invention to provideclopidogrel in a form which is easy to purify and stable and may beprocessed readily even at an industrial scale. In addition, interactionwith common drug carriers, additives and processing aids should beavoided where possible.

Contrary to the disclosure of EP-A-0 281 459, it has now been foundsurprisingly that the salt of a sulfonic acid with clopidogrel issuitable under certain conditions for preparing pharmaceuticalformulations.

The present invention therefore relates to the salt of a sulfonic acidwith clopidogrel at least part of which is present in crystalline form.The present invention further relates to the salt of a sulfonic acidwith clopidogrel which is preparable by precipitating the salt from aclopidogrel solution, the solvent comprising a hydrocarbon and/or anether.

According to the invention, a racemic mixture of the two clopidogrelisomers may be used as the clopidogrel. Alternatively, it is possible touse the pure isomers, the (S)-(+) clopidogrel isomer being preferred.

According to the invention, it has now been found surprisingly that,contrary to the teaching of EP-A-0 281 459, it is possible toincorporate the salt of a sulfonic acid with clopidogrel intopharmaceutical formulations and especially into pharmaceuticalformulations for oral administration. Therefore, the invention alsocomprises using the salt of a sulfonic acid with clopidogrel forpreparing a pharmaceutical formulation and pharmaceutical formulationscontaining such a salt.

The salt of the invention is crystalline at least in part and preferablycompletely crystalline. In this form, the salt may be purified moreeasily than in the amorphous form disclosed in EP-A-0 281 459. Inaddition, it is easier to process crystalline salt into pharmaceuticalformulations.

According to the invention, it has also been found that the desired andespecially the crystalline salts of a sulfonic acid with clopidogrel maybe prepared easily and in a form advantageous for further processinginto a pharmaceutical formulation by precipitating the salt from asolution of clopidogrel if the solvent comprises a hydrocarbon and/or anether. Preferably, the solvent comprises toluene, dioxane,methyl-tert-butyl ether (MTB ether) and/or diethyl ether. It isespecially preferred to use mixtures of toluene and acetone, dioxane andethyl acetate or MTB ether, ethyl acrylate and isopropanol.

For example, the clopidogrel base may be dissolved in toluene and thedesired salt precipitated by adding a sulfonic acid solution, forexample a benzene sulfonic acid solution in acetone. In anotherembodiment, both the clopidogrel base and the sulfonic acid, for examplebenzene sulfonic acid, may be dissolved in dioxane, mixed and thedesired salt precipitated by adding ethyl acetate. In yet anotherembodiment, both the clopidogrel base and the sulfonic acid, for exampletoluene sulfonic acid, may be dissolved in ethyl acetate, mixed and thedesired salt precipitated by adding MTB ether and isopropanol.

According to the method described above, the salt of a sulfonic acidwith clopidogrel may be obtained in good yield and purity so that thissalt is particularly well suited for preparing pharmaceuticalformulations, especially when it is present in crystalline form.

Methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid,toluene sulfonic acid, such as toluene sulfonic acid and naphthalenesulfonic acid, e.g. α-naphthalene sulfonic acid, are examples of thesulfonic acids used for the salts of the invention. Benzene sulfonicacid and toluene sulfonic acid are preferred.

It has also been found that the salt of a sulfonic acid with clopidogrelhas particularly advantageous properties with regard to crystallinity ifit contains solvent molecules. The solvent molecules intercalated insolvate form in the salt originate from the solution from which the saltwas precipitated. Preferably, the salt contains toluene or dioxane.

The salt of the benzene sulfonic acid with clopidogrel precipitated fromtoluene contains toluene molecules.

The 10 most intensive peaks of the X-ray powder spectrum of this salthave the following 2θ values: Relative intensity 2θ 99.11 10.80 100.0012.08 96.77 16.09 62.57 16.66 84.58 20.22 93.53 21.50 66.00 22.56 78.3322.91 81.82 23.45 56.15 24.92

The X-ray powder spectrum which was obtained with a STEO STADI Ptransmission diffractometer using copper Kα radiation is shown in theattached FIG. 1.

The benzene sulfonic acid salt precipitated from dioxane containsdioxane molecules. The 10 most intensive peaks of the X-ray powderspectrum of this salt have the following 2θ values: Relative intensity2θ 51.66 10.78 54.15 10.87 90.13 12.13 50.83 14.34 50.27 16.43 76.0321.57 81.19 22.87 100.00 23.06 54.18 23.72 54.05 25.17

The X-ray powder spectrum of this salt measured as described above isshown in the attached FIG. 2.

The partially crystalline salt of the toluene sulfonic acid withclopidogrel shows the X-ray powder spectrum measured as above as shownin the attached FIG. 3. The 10 most intensive peaks of the X-ray powderspectrum of this salt have the following 2θ values: Relative intensity2θ 80.54 13.13 83.15 13.28 67.75 17.28 70.05 17.64 73.78 18.96 84.6519.21 100.00 19.48 75.95 19.87 71.09 20.12 86.48 25.06

In addition, it was found that the salt of a sulfonic acid withclopidogrel is obtained in particularly high purity when compared withother clopidogrel salts. A besylate salt crystallised from dioxane, forexample, will contain only 0.085% of impurities (according to HPLC).Therefore, the salt of the invention is well suited for preparing pureclopidogrel. The invention thus also relates to a method for purifyingclopidogrel wherein contaminated clopidogrel or a salt thereof,optionally after release of the clopidogrel base, is converted into thesalt of a sulfonic acid with clopidogrel and, if desired, theclopidogrel base is then released from the isolated salt of the sulfonicacid and/or converted into another salt. It is preferred to use thebesylate salt.

It is a further aspect of the invention to provide clopidogrel or apharmaceutically acceptable salt thereof in a form which is easy toprocess further. In the invention, this is achieved by applying the saltonto a solid adsorbent. As a result, active ingredient particles areobtained which are easy to pour and dose.

A suitable adsorbent is any physiologically and pharmaceuticallyacceptable, preferably particulate solid capable of adsorbingclopidogrel or a salt thereof. Preferably, the solid is a free-flowingpowder which may be processed easily into oral pharmaceuticalformulations.

Examples of physiologically and pharmaceutically acceptable solids are,for example:

-   1. Natural or processed adsorbents from the group of clays (clay    materials) and other earths and minerals, e.g. attapulgites,    aluminium-magnesium silicates (Carrisorb®, Gelsorb®),    magnesium-aluminium silicates (Pharmasorb®Veegum®), magnesium    silicates (talcum), calcium silicates, bentonites, kaolin, magnesium    trisilicates, montmorillonites, china clays (bolus), sepiolites    (meerschaum)-   2. Silica gels, kieselguhr, silicic acids-   3. Colloidal (highly disperse) silicic acids (hydrophobic or    hydrophilic Aerosile®, Cab-o-sile®)-   4. Celluloses, modified celluloses, finely and micro-crystalline    celluloses and cellulose derivatives, cellulose acetate, cellulose    fatty acid esters, cellulose nitrates, cellulose ethers    (carboxymethyl celluloses, ethyl celluloses, hydroxyethyl    celluloses, hydroxypropyl celluloses, methyl celluloses, methylethyl    celluloses, methylhydroxypropyl celluloses)-   5. Sugars and sugar derivatives (mono- and polysaccharides),    lactoses, dextranes, dextrose, cyclodextrines-   6. Native maize, rice, tapioca, wheat and potato starches and    derivatives thereof, dextrines, pre-gelatinised, fully or partially    hydrolysed starches-   7. Solid polyols, especially mannitol or sorbitol-   8. Polyacrylates, acrylic acid polymers or copolymers-   9. Phosphates, sulfates, carbonates, gluconates, oxides of alkaline    or alkaline earth metals as well as physiologically acceptable heavy    and transition metals-   10. Guar flour, guar gum-   11. Locust bean flour (carob flour, carob gum)-   12. Alginic acid, alginates and seaweed flour-   13. Tragacanth-   14. Carbo vegetabilis (coal)-   15. Pectines and amylopectines-   16. N-Vinylpyrrolidone polymers such as povidone or crospovidone.

The adsorbents may be used singly or in blends of two or moreadsorbents. Besides the adsorbent, the active ingredient particles ofthe invention may also comprise the usual pharmaceutical adjuvants, forexample for the preparation of direct compression mixtures or for thepreparation of granulates for further processing into drugs.Alternatively, the active ingredient particles may be mixed withsuitable adjuvants after preparation and then processed intopharmaceutical formulations.

Especially preferred adsorbents are certain lactoses (e.g. Lactopress®),certain mannitols (e.g. Mannogem®) and certain celluloses (e.g.Celphere®), particularly Lactopress®. A granulate on the basis of silicaprepared by the pyrogenic route, even though possible, is preferably notused as the carrier medium.

Suitable humectants may be used to control desorption. In order toimprove stability, it is possible, for example, to add antioxidants suchas ascorbic acid and salts thereof. Other suitable adjuvants areemulsifiers, solvents and solubilisers.

The active ingredient particles may, for example, be recovered from asolvent wherein the adsorbent is insoluble or poorly soluble and theclopidogrel or the salt thereof is soluble. For this purpose, theadsorbent may be suspended in the solvent. The clopidogrel or the saltthereof may be dissolved directly in the solvent either before or afterthe suspending step. The active ingredient may be added either directlyor as a solution in the same or a different solvent. After that, theactive ingredient particles comprising the clopidogrel or the saltthereof applied on the adsorbent are recovered from the solvent, forexample by evaporating the solvent.

Suitable solvents are all customary solvents wherein the selectedadsorbent is insoluble or poorly soluble and the clopidogrel or the saltthereof is soluble. For example, the solvents described above inconnection with the preparation of the salt may be used.

In an alternative embodiment of the method of the invention forpreparing active ingredient particles, the last stage of the synthesisof clopidogrel is carried out in the presence of the adsorbent. Thismakes it possible to prepare the desired active ingredient particleswithout an isolating intermediate step. It is also possible, forexample, to mix clopidogrel and an acid with the suspension of theadsorbent. In this process, the clopidogrel and the acid may each bedissolved separately in a solvent and added to the suspension eithersimultaneously or one after the other. Alternatively, the clopidogreland the acid may be added to the suspension in pure form. It is alsopossible to premix individual components and to then add them to thesuspension in joint form.

The weight ratio between the adsorbent and the clopidogrel or the saltthereof adsorbed thereupon is not essential for the invention and may beselected by the skilled practitioner depending on the desired use. If itis intended to process the mixture into oral pharmaceuticalformulations, care should be taken that sufficient clopidogrel is coatedon the adsorbent so that the desired dose in the unit dosage form may beobtained. For example, the weight ratio of clopidogrel or the salt ofclopidogrel based on the free clopidogrel base to the adsorbent may bein the range from 2:1 to 1:6 (i.e., for example, 1 part by wt. ofclopidogrel base per 6 parts by wt. of adsorbent), preferably in therange from 1:1 to 1:3.

Preferred salts of the clopidogrel are hydrogen sulfate, hydrochloride,mesylate, besylate, tosylate and napsylate.

The present invention is illustrated, but not limited by the followingexamples.

The X-ray powder spectra in the examples were obtained by means of aSTOE STADI P transmission diffractometer with copper Kα radiation; theNMR data were obtained with the aid of a Varian Unityplus 300 device andthe CHN data by means of a Carlo Erba Analyzer 1106.

EXAMPLE 1

Preparation of Clopidogrel Benzene Sulfonate from Acetone/Toluene

4.0 g (12.5 mmol) of clopidogrel base were dissolved in 30 ml oftoluene. Then 2.0 g (12.5 mmol) of anhydrous benzene sulfonic acid in 10ml of acetone were added. After some time and grinding with a glass rod,the product solidifies and may be drawn off by suction. The product wasdried over night under vacuum at the pump system in the desiccator.

Yield: 67% Melting point 87 to 90° C.

NMR (ppm) 2.35 (toluene) 3.0-3.5 and 3.8-4.3 (4H), 3.79 (3H), 4.8-5.2(1H), 5.69 (1H), 6.6-6.8 (1H), 7.2-8.0 (12H).

The X-ray powder spectrum of this salt is shown in FIG. 1.

Upon further drying until all of the toluene has been removed from thesalt, the crystal structure collapses and amorphous clopidogrel benzenesulfonate is obtained.

EXAMPLE 2

Preparation of Clopidogrel Benzene Sulfonate from Dioxane

To 109.2 g (339.7 mmol) of clopidogrel base dissolved in dioxane, asolution of 53.7 g (339.7 mmol) of anhydrous benzene sulfonic acid in100 ml of dioxane is added with stirring at 10° C. 250 ml of ethylacetate are added to this solution and the solution placed into adeep-freezer over night. The solution is allowed to warm to roomtemperature and the crystallisate removed by suction, followed bywashing with ethyl acetate. The product is dried under vacuum at roomtemperature for 48 hours.

Yield: 71% Melting point 93 to 95° C.

Elementary analysis Calculated for clopidogrel Values (%) besylate * ½dioxane Found C 55.01 55.28 55.03 H 5.00 5.12 4.99 N 2.67 2.62 2.53

NMR (ppm) 3.0-3.5 and 3.8-4.3 (4H), 3.79 (3H), 4.8-5.2 (1H), 5.68-5.72(1H), 6.6-6.8 (1H), 7.2-8.0 (12H), 3.70 (4H; ½ dioxane)

The X-ray powder spectrum of this salt is shown in FIG. 2.

EXAMPLE 3

Preparation of Clopidogrel Toluene Sulfonate from MTB Ether

4.0 g (12.5 mmol) of clopidogrel base are dissolved in 50 ml of ethylacetate. Then a solution of 2.2 g (12.5 mmol) of toluene sulfonic acid(anhydrous) in 30 ml of ethyl acetate is added. About 50 ml of ethylacetate are distilled off under vacuum and 150 ml of MTB ether and 5 mlof isopropanol are added and the residue is stirred until a solid massis obtained. Removal by suction is followed by drying under vacuum atroom temperature.

Yield: 62% Melting point 78 to 82° C.

The X-ray powder spectrum of this salt is shown in FIG. 3.

EXAMPLE 4

Stability Tests

4.1 The stress stability of various salts of the clopidogrel was testedunder different conditions. The salts used were the form II ofclopidogrel hydrogen sulfate (known as the most stable so far),clopidogrel hydrochloride (prepared according to EP 0 281 459),amorphous clopidogrel benzene sulfonate and crystalline clopidogrelbenzene sulfonate (as prepared in the above example 2). The followingtests were conducted:

Stability Under Acidic Conditions

50 mg of each salt were weighed into a volumetric flask (100 ml) and 2ml of 1N HCl were added. Then the flask is kept either at roomtemperature for 5 hours or at 80° C. for 5 hours. After the end of eachexperiment and, optionally, cooling to room temperature, 2 ml of 1N NaOHare added and mobile phase is added up to 100 ml.

The result is determined by means of HPLC.

Stability Under Basic Conditions

50 mg of the salt concerned are weighed into a volumetric flask (100 ml)and 2 ml of 1N NaOH are added. Then the flask is held either at roomtemperature for 5 hours or at 80° C. for 5 hours. After the end of eachexperiment and, optionally, cooling to room temperature, 2 ml of 1N HClare added and mobile phase is added up to 100 ml.

The result is determined by means of HPLC.

Stability Under Oxydative Conditions

50 mg of the salt concerned are weighed into a volumetric flask (100 ml)and 2 ml of 3% H₂O₂ added. Then the flask is kept either at roomtemperature for 5 hours or at 80° C. for 5 hours. After the end of eachexperiment and, optionally, cooling to room temperature, the mobilephase is added up to 100 ml.

The result is determined by means of HPLC.

Stability Under Neutral Conditions

50 mg of the salt concerned are weighed into a volumetric flask (100 ml)and 2 ml of water added. Then the flask is kept either at roomtemperature for 5 hours or at 80° C. for 5 hours. After the end of eachexperiment and, optionally, cooling to room temperature, the mobilephase is added up to 100 ml.

The result is determined by means of HPLC.

Stability Under the Influence of Heat

50 mg of the salt concerned are weighed into a volumetric flask (100 ml)and held at 80° C. for 20 hours. After the end of each experiment andcooling to room temperature, the mobile phase is added up to 100 ml.

The result is determined by means of HPLC.

In all cases, the HPLC measurements were carried out under the followingconditions with UV detection: Column: Hypersil BDS 5 μm, 250 · 4.6 mmMobile phase: Methanol 650 ml 0.05 M 1-octane sulfonic acid-Na salt 350ml (adjusted to a pH of 2.5 with triethyl amine and phosphoric acid)Flow rate: 1 ml/min Temperature Room temperature of the column:Wavelength: 215 nm Injection volume: 20 μl Retention time: approx. 15min.

The results of these tests are summarised in the following tables 1 to4.

Clopidogrel Hydrogen Sulfate TABLE 1 Condition Room temperature 80° C.acidic 0.32% 2.96% alkaline 0.32% 59.48%  oxidising 0.33% 3.50% neutral0.40% 1.63% heat — 0.31%

Clopidogrel Hydrochloride TABLE 2 Condition Room temperature 80° C.acidic 1.86% 3.31% alkaline 1.86% 72.89%  oxidising 1.83% 4.16% neutral1.84% 4.33% heat — 32.43% 

Clopidogrel Benzene Sulfonate (Amorphous) TABLE 3 Condition Roomtemperature 80° C. acidic 0.64% 2.36% alkaline 0.64% 25.04%  oxidising0.83% 2.94% neutral 0.85% 3.01% heat — 11.52% 

Clopidogrel Benzene Sulfonate (Crystalline) TABLE 4 Condition Roomtemperature 80° C. acidic 0.14% 2.76% alkaline 0.14% 28.05%  oxidising0.13% 3.98% neutral 0.19% 4.18% heat — 4.52%

It is evident that, contrary to the teaching of EP 0 281 459, theamorphous clopidogrel benzene sulfonate has a comparable and, underalkaline conditions, even a considerably increased stability incomparison with the hydrogen sulfate and hydrochloride salts ofclopidogrel. In addition, the stability of the crystalline form of theclopidogrel benzene sulfonate is further increased vis-à-vis that of theamorphous form of this salt, especially at room temperature which isimportant for storing pharmaceutical products. Crystalline clopidogrelbenzene sulfonate is even more stable than clopidogrel hydrogen sulfate,so far known as the most stable one and used in pharmaceuticalformulations.

4.2 In addition, the decrease of the clopidogrel hydrogen sulfate,hydrochloride and besylate (crystalline) contents at 40 and 60° C. and75% relative humidity over 15 days was tested. The results are shown inthe attached FIG. 4.

One can see that the besylate salt (clopidogrel benzene sulfonate) hasthe best stability values both at 40 and 60° C.

EXAMPLE 5

Adsorbate of (S)-(+)-Clopidogrel Besylate on Calcium Gluconate asCarrier Material

With vigorous stirring, a solution of 11 g (69.5 mmol) of anhydrousbenzene sulfonic acid in 100 ml of cold anhydrous diethyl ether wasslowly dropped into a solution of 19.7 g (61.4 mmol) of(S)-(+)-clopidogrel in 300 ml of anhydrous diethyl ether at 3° C. Then apremixed slurry of 28 g of calcium gluconate in cold anhydrous diethylether is added slowly. The crystal paste obtained after completion ofthe addition is removed by suction, washed with ice-cold anhydrousdiethyl ether and then dried.

A white free-flowing powder is obtained.

EXAMPLE 6

Adsorbate of (S)-(+)-Clopidogrel Besylate on Silica Gel/Mannitol asCarrier Material

20 g (62.3 mmol) of (S)-(+)-clopidogrel and 11 g (69.5 mmol) ofanhydrous benzene sulfonic acid are reacted in 200 ml of anhydrousdiethyl ether at a temperature of 2 to 3° C. Then a slurry of 2 g ofsilicic acid and 20 g of mannitol in 100 ml anhydrous diethyl ether isslowly added. The adsorbate thus obtained is removed by suction in coldconditions, washed with ice-cold anhydrous diethyl ether and then dried.39 g of a white free-flowing powder are obtained.

EXAMPLE 7

Adsorbate of (S)-(+)-Clopidogrel Mesylate on Silica Gel/Mannitol asCarrier Material

A solution of 5.85 g (60.8 mmol) anhydrous methane sulfonic acid in 100ml of cold anhydrous diethyl ether is slowly (about 30 min.) droppedinto a solution of 19.5 g (60.7 mmol) of (S)-(+)-clopidogrel in 300 mlof anhydrous diethyl ether at 3° C. Then a premixed slurry of 1.95 g ofsilicic acid and 19.5 g of mannitol in cold anhydrous diethyl ether isadded slowly. The adsorbate obtained after completion of the addition isremoved by suction, washed with ice-cold anhydrous diethyl ether andthen dried.

30 of a free-flowing white powder are obtained.

EXAMPLE 8

Adsorbate of (S)-(+) Clopidogrel Mesylate on Mannitol as CarrierMaterial

19.5 g (60.7 mmol) of (S)-(+)-clopidogrel and 5.85 g (60.8 mmol) ofmethane sulfonic acid are reacted in an analogous manner to example 7.Then a premixed slurry of 19.5 g of mannitol in cold anhydrous diethylether is added slowly. The adsorbate obtained after completion of theaddition is removed by suction, washed with ice-cold anhydrous diethylether and then dried.

29.7 g of a free-flowing white powder are obtained.

EXAMPLE 9

Adsorbate of (S)-(+) Clopidogrel on Silica Gel/Maize Starch as CarrierMaterial

A solution of 5 g (15.6 mmol) of (S)-(+)-clopidogrel in anhydrousdichloromethane is slowly dropped into a suspension of 2 g of Aerosil200 in CH₂Cl₂. After one hour, a suspension of 4 g of gelatinised maizestarch in anhydrous dichloromethane is added with stirring. Aftercompletion of the addition, the solvent is drawn off, resulting in apure white solid which is then dried under vacuum for 12 hours.

A pure white, free-flowing powder having a 45.5% load of activeingredient is obtained.

Repetition of this experiment using 8 g of gelatinised maize starchresulted in a free-flowing powder having a 33.3% load of activeingredient.

EXAMPLE 10

Two different methods were used to prepare adsorbates of the clopidogrelsalts. In the first process, the salt is dissolved in a suitable solventand the adsorbent suspended in this solution.

In a second series of experiments, the clopidogrel was dissolved in asuitable solvent, the adsorbent added and the salt precipitated onto thecarrier material.

In all of these experiments, lactose (Lactopress®), mannitol (Mannogem®)and cellulose (Celphere®) were used as adsorbents.

The following experiments were conducted.

Clopidogrel-Salt Adsorbates with Isolation of the Salt

a) Clopidogrel Besylate Adsorbates

1.5 g (3.1 mmol) of clopidogrel besylate are dissolved in 20 ml ofacetone and 1.5 g of adsorbent added. The solvent is drawn off, theresidue briefly slurried with MTB ether and then dried under vacuum.

b) Clopidogrel Hydrochloride Adsorbates

500 mg (1.4 mmol) of clopidogrel hydrochloride are dissolved in 10 ml ofacetone. 500 mg of adsorbent are added and stirred. The solvent is drawnoff and the residue dried under vacuum.

c) Clopidogrel Hydrogen Sulfate Adsorbates

500 mg (1.2 mmol) of clopidogrel hydrogen sulfate are dissolved in 10 mlof acetone. 500 mg of adsorbent are added and stirred. The solvent isdrawn off and the residue dried under vacuum.

Clopidogrel-Salt Adsorbates Without Prior Isolation of the Salts

1. Diethyl ether as the solvent

a) Clopidogrel Besylate Adsorbates

4.018 g (12.5 mmol) of clopidogrel base are dissolved in 20 ml ofdiethyl ether. 6 g of adsorbent and 1.977 g (12.5 mmol) of benzenesulfonic acid are added in 20 ml of ether. The solid product is removedby suction, washed with ether and dried under vacuum.

b) Clopidogrel Mesylate Adsorbates

4.018 g (12.5 mmol) of clopidogrel base are dissolved in 20 ml ofdiethyl ether. 6 g of adsorbent and 1.2 g (12.5 mmol) of methanesulfonic acid are added in 20 ml of ether. The solid product is removedby suction, washed with ether and dried under vacuum.

c) Clopidogrel Hydrochloride Adsorbates

3 g (9.3 mmol) of clopidogrel base are dissolved in 31 ml of diethylether. 3 g of adsorbent are added and hydrogen chloride gas introduced.The solid product is removed by suction, washed with ether and driedunder vacuum.

2. Methyl-tert-butyl ether (MTB ether) as the solvent

a) Clopidogrel Besylate Adsorbates

4.018 g (12.5 mmol) of clopidogrel base are dissolved in 40 ml of MTBether. 6 g of adsorbent and 1.977 g (12.5 mmol) of benzene sulfonic acidare added in 50 ml of MTB ether. The solid product is removed bysuction, washed with MTB ether and dried under vacuum.

b) Clopidogrel Mesylate Adsorbates

4.018 g (12.5 mmol) of clopidogrel base are dissolved in 40 ml of MTBether. 6 g of adsorbent and 1.2 g (12.5 mmol) of methane sulfonic acidare added in 50 ml of MTB ether. The solid product is removed bysuction, washed with MTB ether and dried under vacuum.

EXAMPLE 11

The stability of the adsorbates obtained according to example 10 wastested. The adsorbates kept their powder form at room temperature anddid not change colour over more than two months.

The decrease of the active ingredient content during 15 days of storageat 40 and 60° C., respectively, and 75% of relative humidity wasmeasured. The results are summarised in the following table 5 [contentafter 15 days (initial value normalised to 100%)]. TABLE 5 40° C. 60° C.Clopidogrel hydrochloride Pure salt 93.66 42.54 Lactopress 99.78 54.89Celpher 92.81 43.74 Clopidogrel mesylate Pure salt 97.56 17.11Lactopress 83.33 59.39 Mannogem 105.51 21.76 Clopidogrel besylate Puresalt 103.32 66.48 Lactopress/diethyl ether 106.91 94.47 Lactopress/MTBether 94.74 92.58

It is evident that the adsorbates have improved stability vis-à-vis thefree salts, especially at elevated temperatures.

EXAMPLE 12

Adsorbates prepared according to example 10 may be compressed directlyinto tablets. This is illustrated by the following sample formulations.The amounts of the other adjuvants used in the following examples areknown to a skilled practitioner and may be taken from standard works onthe formulation of tablets, such as Ritschel et al., “Die Tablette”,Editio Cantor—Aulendorf, 2^(nd) ed., 2002.

a) Clopidogrel Besylate Microcrystalline Cellulose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel besylate microcrystalline cellulose adsorbate219.54 mg (which corresponds to 75 mg of Clopidogrel base) Adjuvants(lubricants, fillers, disintegration promoters, ad 275 mg flowregulators, humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness 101 NAbrasion 0.11% Disintegration time 65 sec. Release 100% after 30 min.

The tablets thus obtained may also be provided with a coating such as anenteric coating or a coating to mask the taste.

b) Clopidogrel Besylate Mannitol Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel besylate mannitol adsorbate 219.54 mg (whichcorresponds to 75 mg of Clopidogrel base) Adjuvants (lubricants,fillers, disintegration promoters, ad 275 mg flow regulators,humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness 106 NAbrasion 0.15% Disintegration time 62 sec. Release 100% after 30 min.

The tablets thus obtained may be provided with a coating such as anenteric coating or a coating to mask the taste.

c) Clopidogrel Besylate Lactose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel besylate lactose adsorbate 219.54 mg (whichcorresponds to 75 mg of Clopidogrel base) Adjuvants (lubricants,fillers, disintegration promoters, ad 275 mg flow regulators,humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 96Abrasion 0.21% Disintegration time sec. 76 Release 100% after 30 min.

The tablets thus obtained may be provided with a coating such as anenteric coating or a coating to mask the taste.

d) Clopidogrel Mesylate Mannitol Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel mesylate mannitol adsorbate 194.79 mg (whichcorresponds to 75 mg of Clopidogrel base) Adjuvants (lubricants,fillers, disintegration promoters, ad 275 mg flow regulators,humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 98Abrasion 0.21% Disintegration time sec. 55 Release 100% after 30 min.

The tablets thus obtained may be provided with a coating such as anenteric coating or a coating to mask the taste.

e) Clopidogrel Mesylate Lactose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel mesylate lactose adsorbate 194.79 mg Adjuvants(lubricants, fillers, disintegration promoters, ad 275 mg flowregulators, humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 88Abrasion 0.22% Disintegration time sec. 72 Release 100% after 30 min.

The tablets thus obtained may be provided with a coating such as anenteric coating or a coating to mask the taste.

f) Clopidogrel HCl Lactose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel HCl lactose adsorbate 167.0 mg Adjuvants(lubricants, fillers, disintegration promoters, ad 275 mg flowregulators, humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 95Abrasion 0.20% Disintegration time sec. 75 Release 100% after 30 min.

The tablets thus obtained may be provided with a coating such as anenteric coating or a coating to mask the taste.

g) Clopidogrel HCl Microcrystalline Cellulose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel HCl microcrystalline cellulose adsorbate 167.0mg (corresponds to 75 mg of clopidogrel base) Adjuvants (lubricants,fillers, disintegration promoters, ad 275 mg flow regulators,humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 100Abrasion 0.13% Disintegration time sec. 65 Release 100% after 30 min.

The tablets thus obtained may also be provided with a coating such as anenteric coating or a coating to mask the taste.

-   h) Clopidogrel Hydrogen Sulfate Microcrystalline Cellulose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel hydrogen sulfate microcrystalline cellulose195.75 mg adsorbate (corresponds to 75 mg of clopidogrel base) Adjuvants(lubricants, fillers, disintegration promoters, ad 275 mg flowregulators, humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 108Abrasion 0.12% Disintegration time sec. 78 Release 98% after 30 min.

The tablets thus obtained may also be provided with a coating such as anenteric coating or a coating to mask the taste.

i) Clopidogrel Hydrogen Sulfate Mannitol Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel hydrogen sulfate mannitol adsorbate 195.75 mg(corresponds to 75 mg of clopidogrel base) Adjuvants (lubricants,fillers, disintegration promoters, ad 275 mg flow regulators,humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 110Abrasion 0.13% Disintegration time sec. 80 Release 98% after 30 min.

The tablets thus obtained may also be provided with a coating such as anenteric coating or a coating to mask the taste.

j) Clopidogrel Hydrogen Sulfate Lactose Adsorbate

Clopidogrel tablets having a total weight of 275 mg and the followingcomposition were prepared from the adsorbate by means of directcompression: Clopidogrel hydrogen sulfate lactose adsorbate 195.75 mg(corresponds to 75 mg of clopidogrel base) Adjuvants (lubricants,fillers, disintegration promoters, ad 275 mg flow regulators,humectants)

Characteristics of the compactible mixture and of the tablets:Compressibility and fluidity satisfactory to good Mean hardness N 109Abrasion 0.13% Disintegration time sec. 80 Release 98% after 30 min.

The tablets thus obtained may also be provided with a coating such as anenteric coating or a coating to mask the taste.

1. The salt of a sulfonic acid with clopidogrel at least part of whichis present in crystalline form.
 2. The salt of a sulfonic acid withclopidogrel which is preparable by precipitating the salt from aclopidogrel solution, the solvent comprising a hydrocarbon and/or anether.
 3. The salt according to claim 2 wherein the solvent comprisestoluene, dioxane, methyl-tert-butyl ether and/or diethyl ether.
 4. Thesalt according to claim 2 at least part of which is present incrystalline form.
 5. The salt according to claim 1 wherein the sulfonicacid is selected from the group consisting of methane sulfonic acid,ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid andnaphthalene sulfonic acid.
 6. The salt according to claim 1 whichcontains solvent molecules.
 7. The salt according to claim 5 wherein thesolvent is selected from toluene and dioxane.
 8. The salt according toclaim 7 which is clopidogrel besylate, is present in crystalline formand contains toluene, the 10 most intensive peaks of the X-ray powderspectrum of this salt having the following 2θ values Relative intensity2θ 99.11 10.78 100.00 12.08 96.77 16.09 62.57 16.66 84.58 20.22 93.5321.50 66.00 22.56 78.33 22.91 81.82 23.45 56.15 24.92


9. The salt according to claim 8 which has the X-ray powder spectrumshown in FIG.
 1. 10. The salt according to claim 7 which is clopidogrelbesylate, is present in crystalline form and contains dioxane, the 10most intensive peaks of the X-ray powder spectrum of this salt havingthe following 2θ values Relative intensity 2θ 51.66 10.78 54.15 10.8790.13 12.13 50.83 14.34 50.27 16.43 76.03 21.57 81.19 22.87 100.00 23.0654.18 23.72 54.05 25.17


11. The salt according to claim 10 which has the X-ray powder spectrumshown in FIG.
 2. 12. The salt according to claim 5 which is clopidogreltosylate, the 10 most intensive peaks of the X-ray powder spectrum ofthis salt having the following 2θ values Relative intensity 2θ 80.5413.13 83.15 13.28 67.75 17.28 70.05 17.64 73.78 18.96 84.65 19.21 100.0019.48 75.95 19.87 71.09 20.12 86.48 25.06


13. The salt according to claim 12 which has the X-ray powder spectrumshown in FIG.
 3. 14. A method for preparing a salt according to claim 1wherein the salt is precipitated from a solution of the clopidogrel andthe solvent comprising a hydrocarbon and/or an ether.
 15. A methodaccording to claim 14 wherein the solvent comprises toluene, dioxane,methyl-tert-butyl ether and/or diethyl ether.
 16. A method for purifyingclopidogrel wherein contaminated clopidogrel or a salt thereof,optionally after release of the clopidogrel base, is converted into thesalt of a sulfonic acid with clopidogrel and, if desired, theclopidogrel base is then released from the isolated salt of the sulfonicacid and/or converted into another salt.
 17. The use of a salt accordingto claim 1 for preparing a pharmaceutical formulation.
 18. Apharmaceutical formulation comprising a salt according to claim
 1. 19.Active ingredient particles comprising a solid adsorbent and clopidogrelor a pharmaceutically acceptable salt thereof adsorbed thereon. 20.Active ingredient particles according to claim 19 wherein the salt isselected from the group consisting of hydrogen sulfate, hydrochloride,mesylate, besylate and tosylate and napsylate.
 21. Active ingredientparticles according to claim 19 wherein the adsorbent is Lactopress. 22.The use of active ingredient particles according to claim 19 forpreparing a pharmaceutical formulation.
 23. A pharmaceutical formulationcomprising active ingredient particles according to claim
 19. 24. Amethod for preparing active ingredient particles as defined in claim 19,comprising the recovery of the active ingredient particles from asolvent in which the adsorbent is insoluble or poorly soluble and theclopidogrel or the salt thereof is soluble.
 25. A method according toclaim 24 comprising suspending the adsorbent in the solvent, dissolvingthe clopidogrel or the salt thereof in the solvent and recovering theactive ingredient particles.
 26. A method according to claim 24 whereinthe active ingredient particles are recovered by evaporation of thesolvent.
 27. A method according to claim 24 wherein the clopidogrel andan acid are mixed with the suspension of the adsorbent.
 28. A methodaccording to claim 24 wherein the last stage of the synthesis ofclopidogrel or a pharmaceutically acceptable salt thereof is carried outin the presence of the adsorbent.